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Extensive research suggests that the trace element selenium (Se) may protect against prostate cancer (PCa) and that the cancer chemopreventive activity may depend on the form of selenium administered. Currently, the SELECT study (JNCI 97: 94-102, 2005) is validating the PCa preventive efficacy of seleno-methionine (Se-Met) in North American men. Our recent work has shown that methylseleninic acid (MSeA) is more active than Se-Met against human PCa xenograft growth in nude mice (Carcinogenesis, in press). Here we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) primary carcinogenesis model to establish the chemoprevention efficacy of MSeA intervention initiated at different stages of PCa development. Male C57BL6 TRAMP mice received a daily oral dose (5 times per week) of 3 mg Se/kg body weight as MSeA beginning at 10 (N=31) or 16 weeks of age (N=30) or received placebo (water) (N=31) starting at the same time points. Mice were given ad libitum access to purified AIN-93M pellets and water. Groups were followed until disease burden necessitated euthanasia or mice reached a predetermined termination age. Blood was collected prior to euthanasia and urogenital (GU) tracts, lungs, kidneys, livers and spleens as well as any visible tumors were removed, weighed and fixed in 10% neutral-buffered formalin. TRAMP mice receiving MSeA at 10-weeks of age survived longer compared to the placebo group (Kaplan-Meier, log rank χ2 = 5.210, df =1, p = 0.0225): median survival time was 45 weeks compared to 40.5 weeks in the placebo group. In the 16-week cohort, median survival time was 41 weeks, not different compared to the placebo group (log rank χ2 = 2.192, df =1, p = 0.1387). GU tract weights were significantly lower in both MSeA-supplemented groups compared to mice receiving placebo, with no difference found between the two cohorts receiving MSeA. In wild-type mice that received 3 mg/kg body weight MSeA (N=9) or placebo (N=10) from 10 weeks of age, there was no significant body weight difference between those receiving MSeA or placebo across the study (P=0.159), indicating that long-term MSeA treatment was well tolerated. Ongoing histopathological analyses of prostate tumors and tissues will provide insight into the relationship between initial age of MSeA treatment and subsequent lesion responses. In summary, results from this study indicate that treatment with MSeA initiated at the stage of prostatic intraepithelial neoplasia (10 weeks of age) increases survival time in TRAMP mice to a greater extent than the same dose initated at a more advanced stage of prostate carcinogensis (16 weeks of age). (grant support: NCI CA126880 and CA95642)

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA